Mary Pay

A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease

Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

Alzheimer’s disease can be accurately diagnosed in very mildly impaired individuals

BackgroundThe growing propensity to diagnose AD in individuals with very mild cognitive impairment increases the danger of false-positive diagnostic errors. Unfortunately, there is little systematically acquired information about the accuracy of the AD diagnosis in very mildly impaired patients. Objective To determine the accuracy of the diagnosis of AD in very mildly impaired patients and to identify objective measures that effectively distinguish these patients from elderly normal controls (NC). Methods Consecutive patients with Mini-Mental State Examination scores of ≥24 who received a clinical diagnosis of AD were evaluated annually for at least 3 years. The initial diagnosis was verified or refuted by autopsy or by information obtained in subsequent evaluations. Initial neuropsychological test scores of verified AD patients were compared with those of NC subjects to identify effective diagnostic measures. Results The diagnosis of AD was confirmed in 98 of 110 (89%) very mildly impaired patients (33/36 by autopsy, 65/74 by disease progression). The diagnosis was inaccurate in 12 patients (11%): Seven were subsequently diagnosed with other neurologic disorders, and five were ultimately found to be normal. Neuropsychological measures of delayed recall, verbal fluency, and global cognitive status (i.e., Mattis Dementia Rating Scale) provided excellent sensitivity (≥96%) and specificity (≥93%) for differentiating between very mildly impaired AD patients and NC subjects. Conclusions When comprehensive assessment procedures are employed, AD can be diagnosed with reasonably high accuracy in very mildly impaired individuals. However, the dementia evaluation should be repeated after approximately 1 year to ensure the accuracy of the initial diagnosis.

Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease

IMPORTANCE Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. OBJECTIVE To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. MAIN OUTCOMES AND MEASURES Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. RESULTS Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease

Nerve growth factor (NGF) is an endogenous neurotrophic‐factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimers disease (AD), but safe and effective delivery has proved unsuccessful.

Rapidly progressive dementia in a patient with the Lewy body variant of Alzheimer's disease

A 65-year-old woman presented with a mild memory impairment, spatial disorientation, and poor task initiation. Progression was rapid over 3 months. She developed severe apathy, delusions, extrapyramidal features, and psychometrically quantified cognitive deterioration. Her brain showed many neocortical neuritic plaques and neurofibrillary tangles along with neocortical and brainstem Lewy bodies and temporal lobe spongiform vacuolization. This case is the most rapid deterioration documented of a patient with Alzheimers disease and Lewy bodies.

Carbidopa/levodopa and selegiline do not affect platelet mitochondrial function in early parkinsonism

Article abstract—Previous studies have demonstrated impaired complex I activity in platelets from Parkinsons disease (PD) patients who were receiving levodopa and other medications for their disease. Eleven patients with early PD underwent three sequential plateletphereses: while on no medication, after receiving carbidopdevodopa for 1 month, and after receiving carbidopdlevodopa plus selegiline for 1 additional month. As expected, carbidopa/levodopa and selegiline significantly improved motor function in these patients. Treatment with carbidopa/levodopa alone and carbidopa/levodopa plus selegiline did not affect the activities of complexes I, II/III, and IV and citrate synthetase. These observations support the hypothesis that impaired complex I activity in PD patients is a characteristic of the disease and not due to medications.

Nerve growth factor gene therapy for Alzheimer's disease.

Materials and Methods This is a Phase I clinical trial to be conducted in 8 people with early Alzheimer’s disease. Subjects with a diagnosis of probable AD undergo skin biopsies to establish culture of primary fibroblasts. The fibroblasts are then genetically modified to produce and secrete human NGF using retroviral vectors. After verifying production of NGF in vitro, cells are harvested and implanted into the Nucleus Basalis of Meynert using stereotaxic neurosurgery. Subjects are then evaluated every 2 wk to 3 mo for safety (primary end point). In addition, cognitive function is measured.