Clinicopathological characteristics of freezing of gait in autopsy-confirmed Parkinson's disease.

BACKGROUND: Twenty-five percent to sixty percent of Parkinson's disease (PD) patients reportedly have freezing of gait, leading to impaired mobility, falls, and decreased quality of life. Several factors have been associated with gait freezing in PD patients. We analyze for these factors in autopsy-proven PD patients. METHODS: We performed a chart review of 58 patients with pathologically confirmed PD based on substantia nigra Lewy bodies. Freezing of gait was defined as a score of 1 or more on Item 14 of the Unified Parkinson's Disease Rating Scale or if documented on examination. Serial office notes and scales were used to determine onset and progression of motor and non-motor symptoms. RESULTS: Patients had been followed up for an average of 20 visits over 9 y. The mean onset of gait freezing was 9.3 y from initial motor symptoms. Patients with earlier gait freezing more commonly had initial gait difficulties and developed postural instability, dyskinesias, memory impairment, hallucinations, and vivid dreams earlier during the disease course. Early onset of hallucinations was correlated with more rapid progression of gait freezing. Maximal equivalent levodopa dose was not correlated with earlier onset or progression of gait freezing. Progressive and more severe gait freezing trended toward higher-severity Lewy body disease on postmortem examination. CONCLUSIONS: Early onset and rapid progression of freezing of gait in this cohort were correlated with early cognitive impairment and hallucinations that are potential clinical hallmarks of cortical Lewy bodies. The gradual worsening and severity of gait freezing correlated with the density of cortical Lewy body-containing neurons.

Essential tremor with ubiquitinated intranuclear inclusions and cerebellar degeneration.

BACKGROUND: Essential tremor (ET), a progressive, age-associated disease, is one of the most common neurological disorders. Yet until recently, there had been few postmortem examinations so that the full range of pathological changes associated with this disease has not been catalogued. OBJECTIVES: We report a patient with ET who had a pattern of pathological change which to our knowledge has not previously been reported in ET or another neurological disease. METHODS: Clinical-pathological case report. RESULTS: The patient had adult-onset, non-familial, kinetic arm tremor that gradually worsened. Voice and head tremors were also present. The clinical diagnosis was ET. She died at age 102. On postmortem examination, there was severe segmental loss of Purkinje cells, Bergmann gliosis and numerous torpedoes in the cerebellum. The other outstanding change was the presence of neurons in the cerebral cortex and hippocampus that contained an ubiquitinated, nuclear inclusion. These inclusions were not detected in Luxol fast blue/hematoxylin and eosin-stained sections. CONCLUSIONS: This ET patient had a pattern of pathological change that has not been reported previously. This case further reinforces the view that ET is likely to be a heterogeneous family of degenerative diseases whose underlying pathological anatomy involves the cerebellum.

Rest tremor in advanced essential tremor: a post-mortem study of nine cases.

BACKGROUND: Rest tremor may occur in as many as 30% of essential tremor (ET) patients. It is not clear whether this tremor is a sentinel marker for brainstem Lewy body pathology. Here we report the clinical and post-mortem findings of nine ET cases with upper-extremity rest tremor in the absence of other parkinsonian features. METHODS: All brains had a complete neuropathological assessment. Tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody. RESULTS: All cases had longstanding ET (median duration=42 years) with moderate to severe arm tremor. Rest tremor involved both arms in seven (77.8%) cases and one arm in two cases. The rest tremor score was correlated with the total action tremor score (r=0.69, p=0.04). The number of torpedoes was elevated, and Purkinje cells, reduced. Post-mortem changes in the substantia nigra pars compacta (SNc), caudate, putamen and globus pallidum were minimal, and neither Lewy bodies nor Lewy neurites were evident. CONCLUSIONS: In nine ET brains with upper-extremity rest tremor, neither Lewy body-containing neurons nor Lewy neurites were found on α-synuclein immunostained sections, and other pathological changes in the basal ganglia were minimal. These data support the notion that isolated rest tremor in longstanding ET is not the expression of underlying Lewy body pathology in the SNc.

What were you thinking?: individuals at risk for Huntington Disease talk about having children.

Most of the research on reproduction in those at risk for Huntington Disease (HD) has focused on the impact of genetic testing on reproductive decision-making. The main goal has been to determine whether discovering one is a carrier of the HD mutation changes an individual's or couple's decision to start a family or to have more children. The purpose of this qualitative study was to examine reproductive decision-making in a sample of individuals at risk for HD who have chosen not to pursue genetic testing. PHAROS (Prospective Huntington At Risk Observational Study) is a multi-site study that aims to establish whether experienced clinicians can reliably determine the earliest clinical symptoms of HD in a sample of individuals at 50% risk who have chosen not to pursue genetic testing. Data for this article were obtained from unstructured open ended qualitative interviews of a subsample of individuals participating in the PHAROS project. Interviews were conducted at six PHAROS research sites across the United States. In this paper, the research team used qualitative descriptive methods to construct and explore reproduction decision-making in three groups of people: 1) those who knew of their risk and decided to have children; 2) those who had children before they knew of their risk, and 3) those who chose not to have children based on their risk. We discuss the delicate balance health care professionals and genetic counselors must maintain between the benefits of providing hope and the dangers of offering unrealistic expectations about the time in which scientific advances actually may occur.

Older onset essential tremor: More rapid progression and more degenerative pathology.

There are few data on rate of progression in essential tremor (ET). To quantify the rate of tremor progression in a cross-sectional sample of 348 ET cases in an epidemiological study; characterize the relationship between age of tremor onset and rate of tremor progression in that sample; and characterize the relationship between age of tremor onset, rate of tremor progression, and severity of underlying brain changes in 9 cases from a brain repository. Rate of tremor progression was defined as tremor severity / duration. The degeneration index = number of torpedoes per section / Purkinje cell linear density. In the epidemiological study, older age of tremor onset was associated with faster rate of tremor progression (P < 0.001). In the brain repository, older age of tremor onset was associated with higher degeneration index (P = 0.037), and higher degeneration index was associated with faster rate of tremor progression (P = 0.018). In a large clinical sample, older age of onset was associated with more rapid tremor progression. In a brain bank, older age of onset was associated with more degenerative pathology in the cerebellum. As in several neurodegenerative disorders, in older onset cases, it is possible that the disease advances more rapidly.

Torpedoes in Parkinson's disease, Alzheimer's disease, essential tremor, and control brains.

Purkinje cell axonal swellings ("torpedoes"), described in several cerebellar disorders as well as essential tremor (ET), have not been quantified in common neurodegenerative conditions. The aim of this study was to quantify torpedoes Parkinson's disease (PD) and Alzheimer's disease (AD) compared with ET and control brains. Brains included 40 ET cases (34 cerebellar ET, 6 Lewy body variant of ET) and age-matched comparison brains (21 AD, 14 PD/diffuse Lewy body disease, 25 controls). Torpedoes were counted in 20 x 25 mm cerebellar cortical sections stained with Luxol Fast Blue/Hematoxylin and Eosin. The median number of torpedoes in cerebellar ET (12) was 12x higher than that of controls (1) and nearly 2.5x higher than in AD (5) or PD/DLBD (5) (all P < or = 0.005). Furthermore, in a logistic regression model that adjusted for age and Alzheimer's-type changes, each torpedo more than doubled the odds of having cerebellar ET (Odds ratio(cerebellar ET vs. control) = 2.57, P = 0.006), indicating that the association between increased torpedoes and cerebellar ET was independent of these Alzheimer's-type changes. Although torpedoes are increased in AD and PD, as well as cerebellar ET, the magnitude of increase in cerebellar ET is greater, and cannot be accounted for by concomitant AD or PD pathology.

Spectrum of gait impairments in presymptomatic and symptomatic Huntington's disease.

The purpose of this study was to quantify gait impairments in presymptomatic and symptomatic Huntington's disease (HD) subjects, and examine sensitivity of gait measures. Our sample (n = 65) included presymptomatic mutation carriers (PMC) (n = 15), symptomatic HD subjects (SHD) (n = 30) and healthy controls (n = 20). Participants were requested to walk at their preferred speed on a computerized walkway that recorded spatiotemporal variables. We administered the Unified HD Rating Scale (UHDRS) for PMC and SHD. PMC demonstrated decreased gait velocity (P < 0.01), stride length (P < 0.008), and increased time in double support (P < 0.001); and demonstrated higher variability in stride length (P < 0.01) and step time (P < 0.004) compared with controls. These impairments worsened with increasing disease severity for SHD. Gait impairments were correlated with predicted years to onset in PMC (velocity = -0.65; cadence = -0.70, step time = 0.71) and demonstrated high sensitivity and specificity in distinguishing between controls and mutation carriers. In contrast, UHDRS scores did not reveal impairments in gait and balance. Gait bradykinesia and dynamic balance impairments begin in the presymptomatic stage of HD and continue to worsen in the symptomatic stages. Gait measures are sensitive in differentiating between mutation positive and negative individuals even when impairments were not detected by clinical neurological examination. (c) 2008 Movement Disorder Society.

Neuropathological changes in essential tremor: 33 cases compared with 21 controls.

Despite its being one of the most commonly observed neurological disorders, neuropathological studies of essential tremor (ET) are rare. There have been surprisingly few autopsy studies and even fewer case-control comparisons. The primary objective was to describe and quantify the pathological changes in 33 ET and 21 control brains. A secondary objective was to correlate clinical and pathological features. We examined autopsy tissue from the Essential Tremor Centralized Brain Repository. Eight (24.2%) of the 33 ET brains had Lewy bodies in the brainstem, mainly in the locus ceruleus. However, the majority of ET brains (25/33, 75.8%) had no Lewy bodies, but had pathological changes in the cerebellum. The mean number of Purkinje cells per 100x field was reduced in ET cases without Lewy bodies (6.6 +/- 2.4 versus 9.6 +/- 3.4, P < 0.01), and there were approximately 7x more Purkinje cell torpedoes per section (12.6 +/- 7.9 versus 1.7 +/- 1.4, P < 0.001) compared to controls. ET cases without Lewy bodies also had degeneration of the dentate nucleus (two cases). Other findings in ET cases were Purkinje cell heterotopias and dendrite swellings. Lewy body ET cases were older than ET cases without Lewy bodies. Several trends were observed in ET cases without Lewy bodies, including a younger age of onset of tremor and higher proportions with gait difficulty and family history of ET. The pathological changes of ET seem to be heterogeneous and degenerative. The majority have cerebellar changes without Lewy bodies; a smaller proportion has brainstem Lewy bodies. The clinical differences between cases with versus without Lewy bodies require additional study.

Harris-Benedict equation estimations of energy needs as compared to measured 24-h energy expenditure by indirect calorimetry in people with early to mid-stage Huntington's disease.

Weight loss and energy metabolism are important clinical research areas in understanding the disease mechanisms in Huntington's disease. Having an accurate method to estimate expected total energy expenditure would likely facilitate the development of studies about these features of the disease. The Harris-Benedict equation is a formula commonly used to estimate basal energy expenditure of individuals, adjusted for height, weight, age and gender. This estimate is then multiplied by a physical activity factor to estimate total daily energy needs to maintain the given weight. Data from 24-h indirect calorimetry was utilized to derive an adjustment formula for the physical activity factor of the Harris-Benedict equation for 13 early to mid-stage Huntington's disease patients. The adjusted activity factor provided the most accurate estimate of energy needs. This adjusted formula can be used in clinical assessments of Huntington's disease patients, as well as in research studies when indirect calorimetry has not been performed.

Living at risk: concealing risk and preserving hope in Huntington disease.

Much of the qualitative research on Huntington disease has focused on the genetic testing aspects of HD. The overall purpose of this qualitative study was to gather information about the everyday experience of living with the risk of developing Huntington disease in a sample of individuals at risk for HD who have chosen not to pursue genetic testing. Data for this article was obtained from unstructured, open-ended qualitative interviews of a sample of people participating in the PHAROS study. PHAROS, the Prospective Huntington At-Risk Observational Study, is a multi-site study that aims to establish whether experienced clinicians can reliably determine the earliest clinical symptoms of Huntington disease in individuals at 50% risk for HD who have chosen not to undergo genetic testing. Interviews were conducted at six PHAROS research sites across the United States. In this paper, the research team used qualitative description to construct and explore two main themes: (1) careful concealment of risk as an act of self-preservation and (2) preserving hope.

Huntington's disease. Part 3: family aspects of HD.

Research into the experience of the Huntington's disease (HD) family caregiver has established that HD carers experience a number of unique obstacles within their caregiving role. This appears to be due to the chronic nature of the disease, both in terms of genetic inheritance and the prolonged disease process itself. Moreover, due to the complex, physical, neurological, psychiatric and genetic elements of HD, service provision may often be unsuitable leaving family members burdened with the main responsibility of care. The complex nature of HD requires service providers, researchers and policy makers to consider each case on an individual basis, thus tailoring service provision to the user and their family's unique requirements.

Huntington's disease: a caring approach to the end of life.

This article describes the challenges of end-of-life care encountered in a specialized long-term care program for people with Huntington's disease (HD). The Promoting Excellence in End-of-Life Care Huntington's Disease Workgroup defines the initiation of palliative care as the point at which independent living is no longer possible. Mobility and lifestyle accommodations for people in the nursing home setting with an early-onset disease are a major feature of this program. The primary end-of-life considerations are advance directives decision-making and anticipating end-stage care needs. Disease progression, denial, family conflict, and clinician blind-spots may impede the development of timely advance directives. The unpredictable and idiosyncratic nature of disease progression impacts decision making for end-of-life care settings and approaches: hospitalization, nursing home stay, and in-house hospice care are the available options. The Workgroup has delineated several priority areas for patient care in HD: autonomy; dignity; meaningful social interaction; communication; comfort; safety and order; spirituality; enjoyment, entertainment and well-being; nutrition; and functional competence. This review also includes a description of the program features in each of these areas.

Survey of community-based programs serving U.S. families with Huntington's disease: perceived barriers and facilitators in the residential placement process.

This article describes the contours of the residential care placement experience for social service staff health care providers, and their client families of patients with Huntington's disease. The purpose of this study was to determine the factors, conditions, and barriers encountered by outpatient clinical staff and families in the transition to skilled nursing care. A Long-Term Care Contact Survey was developed to (a) gather information about long-term care referral sites; (b) determine the factors considered in choosing a facility; (c) describe the factors that hindered the transition to long-term care; (d) describe conditions prior to institutionalization; and (e) determine research interest. The study found that large cohorts of patients with Huntington's disease in residential care are scarce. A lack of confidence in the available options suggests the need for increased support for educational and social services to facility staff Speech/swallowing therapy and physical therapy as placement facilitators reflect salient issues of latter stages of the disease, implicating funding support needs. Families facing this transition require long-term guidance for financiail, caregiving, and psychosocial issues.

Making a measurable difference in advanced Huntington disease care.

Neurologists' role in the care of people with advanced Huntington disease (HD) (total functional capacity <7), often limited by a lack of clinical research to support good practice, includes the following: (1) provide comprehensive health records to an interdisciplinary care staff before admission to a more intense care setting (home health services, day program, assisted living, group home, long-term skilled nursing facility, palliative care); (2) consult with and refer to rehabilitation (occupational therapy, physical therapy, speech and language pathology), behavioral and psychiatric professionals for problem-solving strategies, which must be reviewed with direct care staff before implementation; (3) encourage and support qualitative and quantitative interdisciplinary research studies, and randomized controlled studies of nonpharmacologic interventions; and (4) assist in the development of meaningful measures to further document what works to provide a good quality of life for the patient and family and a comfortable thoughtful approach to a good death. Collaborative models of care depend on: (1) clear communication; (2) ongoing education and support programs; with (3) pharmacologic and rehabilitation interventions, always in the context of respect for the person with HD, a preservation of the individuals' dignity, autonomy, and individual preferences.

Essential tremor associated with pathologic changes in the cerebellum.

BACKGROUND: Although essential tremor (ET) is one of the most common neurologic disorders, there have been few postmortem studies. We recently reported postmortem changes (torpedoes and Bergmann gliosis) in the cerebellar cortex in a few ET cases. OBJECTIVE: To describe more extensive postmortem changes in the cerebellum in another ET case. DESIGN: Case report. RESULTS: A 90-year-old woman had a 30-year history of ET. At postmortem examination, there was segmental loss of Purkinje cells, presence of torpedoes, and Bergmann gliosis in the cerebellar cortex. Moreover, there were extensive changes in the dentate nucleus, in the form of neuronal loss, neuronal atrophy, microglial clusters, and reduction in the number of efferent fibers (ie, pallor of the hilum). CONCLUSIONS: The brain in the current case exhibited more marked cerebellar pathologic features than noted in previously reported ET cases and thereby extends the described cerebellar findings in this common, yet pathologically poorly characterized, neurologic disorder.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

IMPORTANCE: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES: Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

Energy balance in early-stage Huntington disease.

BACKGROUND: Huntington disease (HD) is a genetic neurologic disorder. Weight loss is common in HD and is related to progression of the disease, but the cause of weight loss remains unclear. OBJECTIVE: The study objective was to compare 24-h energy expenditure (EE) and energy intake in persons with early midstage HD with those of matched control subjects to determine how HD affects energy balance. DESIGN: EE was assessed in 13 subjects with early-stage HD and in 9 control subjects via indirect calorimetry in a human respiratory chamber. Energy intake was determined by weighing all food provided and all leftovers from an ad libitum diet. Body composition was measured via air-displacement plethysmography. Stage of disease was estimated on the basis of the Unified Huntington's Disease Rating Scale and modified Mini-Mental Status examinations. Regression analysis included all 13 HD subjects; t tests were used for the comparisons between matched HD and control subjects. RESULTS: 24-h EE was 11% higher in the HD subjects than in the control subjects (NS). This difference was due to a higher (P = 0.043) waking metabolic rate, which was related to a significantly greater displacement of the center of mass by HD subjects than by control subjects (P = 0.028). On average, both groups were in positive energy balance and exceeded their energy expenditure by 2510-2929 kJ. CONCLUSIONS: Higher 24-h EE in persons with early midstage HD is due to increased physical activity, both voluntary and involuntary. However, HD subjects are able to maintain positive energy balance when offered adequate amounts of food in a controlled setting.

Essential tremor associated with focal nonnigral Lewy bodies: a clinicopathologic study.

BACKGROUND: Essential tremor is one of the most common neurological diseases. Its links with Parkinson disease (PD) are often debated. There have been few published postmortem studies. OBJECTIVE: To study our first case of essential tremor through the recently established Essential Tremor Centralized Brain Repository. DESIGN: Report of a case of a patient with a diagnosis of severe essential tremor for 46 years who exhibited no signs of parkinsonism. RESULTS: On postmortem examination, gross brain sections showed no abnormalities. Results of microscopic examination of hematoxylin-eosin-stained sections revealed that the locus coeruleus contained multiple Lewy bodies (LBs), although none were found in the substantia nigra, dorsal vagal nuclei, thalamus, substantia innominata, inferior olivary nucleus, or cerebellum. Immunochemical staining using antibodies directed against alpha-synuclein confirmed the presence of many LBs in the locus ceruleus and showed rare LBs in the substantia innominata and dorsal vagal nuclei. There were no LBs in the substantia nigra. CONCLUSIONS: Our patient had a very focal presence of LBs in the locus ceruleus, an anatomically restricted form of LB disease. This study provides support for the link between essential tremor and LB disease and raises the question as to what proportion of patients with essential tremor might have unusual forms of LB disease.

Clinical and pathological characteristics of LRRK2 G2019S patients with PD.

The objective of this study is to describe the neuropathologic findings in three LRRK2 G2019S carriers with Parkinson's disease (PD). We cross-referenced a list of 956 PD individuals that had been previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients. All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy body (LB) pathology, tau inclusions, and amyloid pathology consistent with advanced Alzheimer's disease; one had diffuse cortical LB; and one had only brainstem predominant LB pathology. Cognitive impairment may be a long-term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow-up of LRRK2 G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.